By Konstantinos Kavallieros
COVID-19, the disease caused by the novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), is one that is multifaceted, affecting multiple organ systems, and creating immense difficulties for health care professionals – who are faced with the task of treating it without fully comprehending its pathophysiological mechanisms of action. The elucidation of said mechanisms is crucial in improving the health care response and may lead to the discovery of a range of pharmaceutical targets, aiding the treatment of very sick individuals.
One response which is compromised in COVID-19 is the stress response, both directly and not. Salari et al. (2020) pointed out how addressing psychological disorders is as important as treating physical health concerns to effectively tackle this pandemic. Significantly, they reported the prevalence of stress in the general population at 29.6% indicating the necessity of the ‘development of psychological interventions’ to improve mental health. One can intuit that stress may stem from fear of being infected or infecting others, fear of losing loved ones, emotional and financial insecurity, and more. Added to this, SARS-CoV-2 may also directly activate the neuroendocrine stress response and in this article, the proposed mechanisms, as well as potential therapeutic targets associated with this interaction, will be reviewed.
The adrenal glands seem to play an important role in COVID-19 pathogenesis and interestingly, in the 2003 SARS pandemic, following the lung, the adrenal belonged to the organs with the highest concentration of virus particles (Salari et al., 2020). It is known that at a systemic level, multiple ‘external stressors activate the sympathetic branch of the autonomic nervous system’, as well as the hypothalamo-pituitary-adrenal (HPA) axis (Steenblock et al., 2020). The HPA axis mediates the neuroendocrine component of the stress response via the following mechanism: neurons in the paraventricular nucleus of the hypothalamus release corticotropin-releasing factor (CRF), which once bound to CRF receptors on the anterior pituitary gland, causes release of adrenocorticotrophic hormone (ACTH) (Alschuler, 2016). Downstream activation of the adrenal cortex by ACTH leads to the production of cortisol, the stress hormone. Cortisol mainly functions to boost energy, mobilizing energy resources such as stored energy via hepatic glycogenolysis or lipolysis, preparing the body for a “fight or flight” response. (Herman J et al., 2016).
Although the exact mechanism by which SARS-CoV-2 impacts the HPA axis has yet to be fully understood and articulated, something that will require more time and experimentation, several hypotheses have emerged. To comprehend the following mechanisms, knowledge of the entry route of SARS-CoV-2 into cells is useful. The virus enters via the ACE2 receptor, using its “viral spike (S) glycoprotein” to do so; following antigen-receptor binding, the viral envelope fuses with the cell plasma membrane to allow the viral content to access the cellular machinery (Steenblock et al., 2020).
One of the potential mechanisms through which SARS-CoV-2 activates the HPA axis stems from the findings of Wang L. et al. (2018), who reported the presence of a ‘centrally mediated’ mechanism via which mice with ACE2 overexpression in hypothalamic CRF neurons had decreased cortisol; this to ‘decreased anxiety-like behaviour, when compared to controls’. This was secondary to a stunted HPA axis. Significantly, research into the 2003 SARS pandemic by Kuba K et al. (2005), documented a decreased expression of ACE2 in the lungs and myocardium of infected mice and was corroborated by data showing that patients that died from SARS-CoV had reduced ACE2 in the heart (Oudit GY et al., 2009). It has not yet been sown that ACE2 is downregulated in the hypothalamus, however the above indicates the possibility of a mechanism via which SARS-CoV-2 may lead to HPA axis activation; this is from the simple deduction that reduced expression rather than overexpression of ACE2 will lead to activation rather than suppression of the HPA axis, and thus increased anxiety-like behaviour.
Secondly, a study published in The Lancet by Mehta P et al. (2020), suggests that COVID-19 pathophysiology is associated with increased levels of pro-inflammatory cytokines and an ensuing cytokine storm. Since HPA axis activation is commonly seen in ‘pathologies involving an inflammatory process, including viral infections’, there is a possibility that said cytokine storm may, in part, cause the elevated stress levels observed in those infected with the virus (Raony Í. et al., 2020)
It is evident that research into potential treatments targeting the above may prove very important in the fight against the virus. More specifically, any pharmacological interventions that target neuroendocrine regulatory systems may prove beneficial, including: ‘corticosteroids; ACE inhibitors; or angiotensin receptor blockers’ (Steenblock et al., 2020). Additionally, the utility of treatment that influences ACE2 expression has to be carefully considered as, secondary to its impact on the neuroendocrine stress axis, long-term psychological consequences such as major depressive or anxiety disorders may arise, as documented by G Russel et al. (2019).
References:
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Imperial Bioscience Review 